The present invention relates generally to microfabricated capsules, and more particularly to microfabricated porous capsules for immunological isolation of cell transplants.
Medical researchers have demonstrated that the concept of microencapsulation to provide immunological isolation is valid. The islets of Langerhans, which produce insulin in mammals, have been transplanted between different species. For example, pig islets have been transplanted into diabetic dogs to produce insulin. However, these unprotected islets function only for a short time before the immune system of the host kills the donor cells.
Encapsulation of islets in order to protect them from immune system macromolecules has been shown to prolong the survival of donor cells. By using various means of encapsulation, insulin production from pig islets has been maintained for over one hundred days in dogs. Encapsulation methods to date have used semipermeable amorphous organic polymeric membranes, sintered together particles, and intermeshed ceramic needles. Significant problems have been encountered, however, limiting the useful life of these capsules to not much more than one hundred days.
The two principal problems with existing capsules are inadequate mechanical strength and insufficient control of pore size and pore distribution. Specifically, if the thickness of an organic membrane capsule wall is increased to provide the required mechanical strength, molecules cannot diffuse through the capsule wall quickly enough to provide the appropriate physiological response when needed. Moreover, if the size and distribution of pores cannot be controlled, such as with sintered together particles or amorphous polymeric membranes, there is a high probability of oversized or overlapping pores which could provide an opening large enough for immunological macromolecules to enter the capsule.
An improved capsule should combine mechanical strength with the ability to allow the free diffusion of small molecules such as oxygen, water, carbon dioxide, and glucose, while preventing the passage of larger molecules such as the immunoglobins and major histocompatibility (MHC) antigens. Also, the intermediate sized molecular products, such as insulin, produced by the donor cells should be able to diffuse out to the host at a sufficient rate to provide the needed metabolic function. Such a device would provide a longer lasting alternative to presently available capsules, and eliminate the need for anti-rejection drugs by the simple strategy of physically isolating the transplanted cells so that no immunological reaction can take place. Cells from any source could then be implanted in any host. Tissue matching of donor to recipient would not be a concern.
The ideal structure would be a capsule made of a biologically compatible material with sufficient mechanical strength to form a very thin membrane having at least a region with uniformly sized and spaced holes that are just large enough to let the desired biologically active molecular product through, while totally blocking the passage of all larger immunological molecules. Such a structure cannot be made from a polymer with an amorphous molecular structure, by sintering together particles, or by intermeshed ceramic needles.
Accordingly, an object of the present invention is to provide a capsule made of a biologically compatible material with sufficient mechanical strength to form a very thin membrane shell having at least a region with approximately uniformly sized and spaced holes in it that are large enough to let the desired biologically active molecular product through, while blocking the passage of all larger immunological molecules, thus providing an immunological isolation of cell transplants contained therein.
It is a further object of the present invention to provide a free standing thin film structure that may be used as a component of such a capsule.
It is another object of the present invention to provide methods for the fabrication of such components and such capsules.
Another object of the invention is to provide a method of filling such capsules.
Yet another object of the invention is to provide an apparatus for filling such capsules.
Still another object of the invention is to provide a method of administering a biologically active molecule to a host organism deficient in endogenous production of said biologically active molecule using such capsules.
Additional objects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the claims.